Research

The
earliest mutations of human life have been observed by research team led by the
Wellcome Trust Sanger Institute and their collaborators. Analyzing genomes from
adult cells, the scientists could look back in time to reveal how each embryo
developed.

﻿Research
team of the Sanger Institute including Professor Young Seok Ju of the Graduate
School of Medical Science and Engineering at KAIST published an article of “Somatic
Mutations Reveal Asymmetric Cellular Dynamics in the Early Human Embryo” in Nature on March 22.

The study shows that from the two-cell stage of the human embryo, one of these cells becomes more dominant than the other and leads to a higher proportion of
the adult body.

A longstanding question for researchers has been what happens in the very early
human development as this has proved impossible to study directly. Now,
researchers have analyzed the whole genome sequences of blood samples
(collected from 279 individuals with breast cancer) and discovered 163
mutations that occurred very early in the embryonic development of those
people.

Once identified, the researchers used mutations from the first, second and
third divisions of the fertilized egg to calculate which proportion of adult
cells resulted from each of the first two cells in the embryo. They found that
these first two cells contribute differently to the whole body. One cell gives
rise to about 70 percent of the adult body tissues, whereas the other cell has
a more minor contribution, leading to about 30percent of the tissues. This
skewed contribution continues for some cells in the second and third generation
too.

Originally pinpointed in normal blood cells from cancer patients, the
researchers then looked for these mutations in cancer samples that had been
surgically removed from the patients during treatment. Unlike normal tissues
composed of multiple somatic cell clones, a cancer develops from one mutant
cell. Therefore, each proposed embryonic mutation should either be present in
all of the cancer cells in a tumor, or none of them. This proved to be the
case, and by using these cancer samples, the researchers were able to validate
that the mutations had originated during early development.

Dr. Young Seok Ju, first author from the Wellcome Trust Sanger Institute and KAIST,
said: "This is the first time that anyone has seen where mutations arise
in the very early human development. It is like finding a needle in a haystack.
There are just a handful of these mutations, compared with millions of
inherited genetic variations, and finding them allowed us to track what
happened during embryogenesis."

Dr. Inigo Martincorena, from the Sanger Institute, said: "Having
identified the mutations, we were able to use statistical analysis to better
understand cell dynamics during embryo development. We determined the relative
contribution of the first embryonic cells to the adult blood cell pool and
found one dominant cell - that led to 70 percent of the blood cells - and one
minor cell. We also sequenced normal lymph and breast cells, and the results
suggested that the dominant cell also contributes to these other tissues at a similar
level. This opens an unprecedented window into the earliest stages of human
development."

During this study, the researchers were also able to measure the rate of
mutation in early human development for the first time, up to three generations
of cell division. Previous researchers had estimated one mutation per cell
division, but this study measured three mutations for each cell doubling, in
every daughter cell.

Mutations during the development of the embryo occur by two processes - known
as mutational signatures 1 and 5. These mutations are fairly randomly
distributed through the genome, and the vast majority of them will not affect
the developing embryo. However, a mutation that occurs in an important gene can
lead to disease such as developmental disorders.

Professor Sir Mike Stratton, lead author on the paper and Director of the
Sanger Institute, said: "This is a significant step forward in widening
the range of biological insights that can be extracted using genome sequences
and mutations. Essentially, the mutations are archaeological traces of
embryonic development left in our adult tissues, so if we can find and
interpret them, we can understand human embryology better. This is just one
early insight into human development, with hopefully many more to come in the
future."